Premium
An In Vitro and In Vivo study of BNAP: A Novel Peripherally Selective μ‐opioid Receptor Antagonist
Author(s) -
Williams D,
Yuan Y,
Stevens D,
Zhang Y,
Dewey W,
Akbarali H
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.929.2
Subject(s) - antagonist , pharmacology , morphine , nap , opioid , chemistry , opioid antagonist , potency , in vivo , opioid receptor , receptor , μ opioid receptor , receptor antagonist , medicine , in vitro , (+) naloxone , biology , biochemistry , microbiology and biotechnology , neuroscience
Activation of μ‐opioid receptors (MORs) on enteric neurons during opioid treatment inhibits gastrointestinal peristalsis and leads to constipation. This is the most significant side affect associated with opioid treatment. Peripherally active MOR antagonists can minimize constipation without affecting analgesia. Previously, we described the 6β‐Naltrexamine derivative NAP as a novel peripherally selective MOR antagonist. NAP was 300x more potent than methylnaltrexone at improving intestinal motility in morphine tolerant mice. However, NAP partially antagonized morphine antinociception in the mouse tail‐flick assay. Efforts to reduce CNS activity led to the development of BNAP. Radioligand binding studies show BNAP maintained high MOR affinity (K i = 0.76 ± 0.09 nM). In the mouse tail flick assay BNAP (10mg/kg) did not antagonize morphine‐induced antinociception. BNAP also competitively inhibited morphine‐induced contractions in circular muscle preparations from the mouse distal and proximal colon. Both NAP and BNAP antagonized morphine‐induced contractions with equal efficacy at the doses tested (1, 10, and 100 nM). Interestingly, they were 10x more potent in the proximal colon. This suggests differences in MOR receptor density or splice variants between proximal and distal colon. In conclusion, BNAP is a more peripherally selective MOR antagonist than NAP and has equal potency in isolated tissue preparations. Thus, BNAP is a suitable lead for further study and development as a novel peripherally selective MOR antagonist. Supported by DA024009, DA024002, and DA007027.